CN113444181B - 抗kl-6双特异性抗体及基因、重组载体、药物、试剂盒 - Google Patents
抗kl-6双特异性抗体及基因、重组载体、药物、试剂盒 Download PDFInfo
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- CN113444181B CN113444181B CN202111018021.2A CN202111018021A CN113444181B CN 113444181 B CN113444181 B CN 113444181B CN 202111018021 A CN202111018021 A CN 202111018021A CN 113444181 B CN113444181 B CN 113444181B
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- Peptides Or Proteins (AREA)
Abstract
本发明公开了抗KL‑6双特异性抗体或其变体、或其功能性片段，所述抗KL‑6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO.1~3所示的氨基酸序列。本发明还提供了基因、重组载体、药物、试剂盒。本发明的抗KL‑6双特异性抗体或其变体、或其功能性片段用于与KL‑6蛋白特异性结合，基因、重组载体用于抗KL‑6双特异性抗体的制备，药物用于治疗KL‑6蛋白引起的相关疾病，试剂盒用于KL‑6蛋白的定量检测。
Description
技术领域
本发明涉及免疫学相关技术领域。更具体地说，本发明涉及一种抗KL-6双特异性抗体或其变体、或其功能性片段及基因、重组载体、药物及试剂盒。
背景技术
双特异性抗体（Bispecific Antibodies，BsAb）是单分子抗体，其兼备两个抗体的抗原结合位点，可以结合两个不同的抗原决定簇，其可以在一个抗原上，也可以在不同的抗原上，而天然抗体只能识别一个抗原表位。抗KL-6双特异性抗体广泛用于临床诊断、影像、疾病预防和肿瘤免疫治疗。
唾液酸化糖链抗原-6（Krebs Von den Lungen-6，KL-6）是一种高分子量的跨膜黏蛋白，在正常上皮细胞中起到润滑和保护的作用。KL-6胞外区由脯氨酸，苏氨酸和富含丝氨酸的（PTS）域和SEA域组成，PTS域，又叫可变数目串联重复序列（VNTR）区，KL-6现在归属为人类MUC1粘蛋白，含有分子量约为200 KDa的唾液酸化糖链，该糖链主要是由PTS域组成，具有被特异性抗体识别的空间结构表位，KL-6的胞内区是高度保守的。
相关研究表明KL-6高水平表达可能与间质性肺疾病（interstitial lungdisease，ILD）、急性肺损伤（acute lung injury，ALI）、放射性肺炎、病毒性肺炎、药物相关性间质性肺炎、肿瘤等疾病有关。研究表明，其通过比较ILD患者、其他肺部疾病患者与健康人血清中KL-6水平，发现ILD患者体内KL-6浓度显著高于肺炎、肺结核、支气管扩张等疾病患者及健康人。因此，KL-6检测可用于鉴别间质性肺疾病和其他肺部疾病，其可作为肺部组织疾病的特异标志物。而且，最新研究发现，KL-6可作为COVID-19的危重型患者和轻型患者长期肺损伤的生物标志物。因此，设计KL-6抗体对于相关疾病诊断、疾病治疗具有较大意义。
发明内容
本发明的一个目的是提供一种抗KL-6双特异性抗体或其变体、或其功能性片段及基因、重组载体、药物及试剂盒，抗KL-6双特异性抗体或其变体、或其功能性片段用于与KL-6蛋白特异性结合，基因、重组载体用于抗KL-6双特异性抗体的制备，药物用于治疗KL-6蛋白引起的相关疾病，试剂盒用于KL-6蛋白的定量检测。
为了实现本发明的这些目的和其它优点，本发明提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 1~3所示的氨基酸序列。
进一步地，所述抗PTS域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 4~6所示的氨基酸序列。
进一步地，所述抗SEA域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 7~9所示的氨基酸序列。
进一步地，所述抗SEA域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO.10~12所示的氨基酸序列。
本发明提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区具有SEQ ID NO. 13所示的氨基酸序列，所述抗PTS域的轻链可变区具有SEQ ID NO. 14所示的氨基酸序列，所述抗SEA域的重链可变区具有SEQ ID NO. 15所示的氨基酸序列，所述抗SEA域的轻链可变区具有SEQ ID NO. 16所示的氨基酸序列。
本发明提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段的重链双可变区具有SEQ ID NO. 17所示的氨基酸序列，所述抗KL-6双特异性抗体或其变体、或其功能性片段的轻链双可变区具有SEQ ID NO.18所示的氨基酸序列。
本发明还提供了编码所述的抗KL-6双特异性抗体或其变体、或其功能性片段的基因。
本发明还提供了包括所述基因的重组载体。
本发明还提供了药物，包括所述的抗KL-6双特异性抗体或其变体、或其功能性片段。
本发明还提供了试剂盒，包括所述的抗KL-6双特异性抗体或其变体、或其功能性片段。
本发明至少包括以下有益效果：
本发明的抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，能够同时特异性识别和结合唾液酸化糖链抗原-6上的PTS域和SEA域，本发明的基因、重组载体用于抗KL-6双特异性抗体的制备，药物用于治疗KL-6蛋白引起的相关疾病，试剂盒能够用于KL-6蛋白的定量检测。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为本发明所述抗KL-6抗KL-6双特异性抗体的结构示意图。
图2为本申请一个实施例中KL-6抗原测定试剂盒的定标曲线，将KL-6抗原用校准品稀释液配制成一系列校准品，浓度分别为0U/mL，1250U/mL，2500U/mL，5000U/mL，10000U/mL。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
本申请的实施例提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 1~3所示的氨基酸序列。
本实施例的双特异抗体、或其变体、或其功能性片段可以是全长抗体，或仅包含两抗原结构域结合部分，如单链抗体(scFv)，或全长抗体与抗原结合部分组成的融合蛋白。在不实质性影响抗体亲和力的前提下，本领域研究人员可以对本实施例的序列替换、添加和/或缺失一个或更多个(例如1、2、3、4、5、6、7、8、9或10个)氨基酸，以获得所述抗体或其功能性片段之序列的变体。SEQ ID NO. 1~3所示的氨基酸序列为GYTFTVYV、ILPSSGYA和ARSTAAGYDY。
在另一些实施例中，所述抗PTS域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQID NO. 4~6所示的氨基酸序列。SEQ ID NO. 4~6所示的氨基酸序列为QAIVHANGNTY、KVS和FQGSHTPYT。
在另一些实施例中，所述抗PTS域的重链可变区具有SEQ ID NO. 13所示的氨基酸序列，即QVQLQQSGPELVKPGASMKISCKASGYTFTVYVLNWVRQRPGQGLEWIGRILPSSGYAAYNAAFKGKTTLTVDKSSSTAYMDVETLTSEDSAVYYCARSTAAGYDYWGQGTTLTVSS。
在另一些实施例中，所述抗PTS域的轻链可变区具有SEQ ID NO. 14所示的氨基酸序列，即DVLMTQIPLSLPVSLGDQASISCKSSQAIVHANGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHTPYTFGSGTKLEIK。
在另一些实施例中，所述抗SEA域的重链可变区的CDR1、CDR2和CDR3分别具有SEQID NO. 7~9所示的氨基酸序列，即GFTFSHYG、IGSRGTYT和ARGEDYRFDVGKGVVY。
在另一些实施例中，所述抗SEA域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQID NO. 10~12所示的氨基酸序列，即ESVDNYGFSF、WIS和QQTKEVPWT。
在另一些实施例中，所述抗SEA域的重链可变区具有SEQ ID NO. 15所示的氨基酸序列，即QVQLQQSGAELVKPGASVKLSCKTSGFTFSHYGMHWFRQAPEKGLEWVAYIGSRGTYTDYNGKFRDKATLTADKSSSTAYLQLSSLTSVDSAVYFCARGEDYRFDVGKGVVYWGQGTTLTVSS。
在另一些实施例中，所述抗SEA域的轻链可变区具有SEQ ID NO. 16所示的氨基酸序列，即DIVMSQSPSSLAVSVGEKVTLSCKSSESVDNYGFSFLEWYLQKPGQSPVLLIYWISNRYTGVPDRFIGSGSATEFTLTISSVQAEDLADYHCQQTKEVPWTFGGGTKLEIK。
本发明提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区具有SEQ ID NO. 13所示的氨基酸序列，所述抗PTS域的轻链可变区具有SEQ ID NO. 14所示的氨基酸序列，所述抗SEA域的重链可变区具有SEQ ID NO. 15所示的氨基酸序列，所述抗SEA域的轻链可变区具有SEQ ID NO. 16所示的氨基酸序列。
本发明提供了抗KL-6双特异性抗体或其变体、或其功能性片段，所述抗KL-6双特异性抗体或其变体、或其功能性片段的重链双可变区具有SEQ ID NO. 17所示的氨基酸序列，即QVQLQQSGPELVKPGASMKISCKASGYTFTVYVLNWVRQRPGQGLEWIGRILPSSGYAAYNAAFKGKTTLTVDKSSSTAYMDVETLTSEDSAVYYCARSTAAGYDYWGQGTTLTVSSAEAAAKEAAAKEAAAKEAAAKAQVQLQQSGAELVKPGASVKLSCKTSGFTFSHYGMHWFRQAPEKGLEWVAYIGSRGTYTDYNGKFRDKATLTADKSSSTAYLQLSSLTSVDSAVYFCARGEDYRFDVGKGVVYWGQGTTLTVSS，所述抗KL-6双特异性抗体或其变体、或其功能性片段的轻链双可变区具有SEQ ID NO. 18所示的氨基酸序列，即DVLMTQIPLSLPVSLGDQASISCKSSQAIVHANGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHTPYTFGSGTKLEIKAEAAAKEAAAKEAAAKEAAAKADIVMSQSPSSLAVSVGEKVTLSCKSSESVDNYGFSFLEWYLQKPGQSPVLLIYWISNRYTGVPDRFIGSGSATEFTLTISSVQAEDLADYHCQQTKEVPWTFGGGTKLEIK。即由依次连接的抗体的轻链双可变区(抗PTS VL-SEAVL-CL)、重链双可变区(抗PTS VH-SEAVH-CH)组成，连接两个重链可变区或轻链可变区的Linker具有如SEQ ID NO. 19所列出的氨基酸序列，即AEAAAKEAAAKEAAAKEAAAKA。
本申请的实施例还提供了编码所述的抗KL-6双特异性抗体或其变体、或其功能性片段的基因，其中，SEQ ID NO.13的基因序列如SEQ ID NO.20所示，SEQ ID NO.14的基因序列如SEQ ID NO.21所示，SEQ ID NO. 15的基因序列如SEQ ID NO.22所示，SEQ ID NO.16的基因序列如SEQ ID NO.23所示，SEQ ID NO. 17的基因序列如SEQ ID NO.24所示，SEQ IDNO.18的基因序列如SEQ ID NO.25所示.
本申请的实施例还提供了包括所述基因的重组载体，将重组载体转入宿主细胞，培养，即可产生抗KL-6双特异性抗体。
本申请的实施例还提供了药物，包括所述的抗KL-6双特异性抗体或其变体、或其功能性片段，可以是用于间质性肺疾病、乳腺癌、前列腺癌、卵巢癌、胰腺癌或结肠癌的药物，药物还可以包括药物学可接受的载体和赋形剂。
本申请的实施例还提供了试剂盒，包括所述的抗KL-6双特异性抗体或其变体、或其功能性片段，试剂盒使用胶乳增强免疫法或化学发光免疫法，结合标准曲线法进行测试。
以下以具体实施例说明。
实施例1：抗人KL-6的抗KL-6双特异性抗体的获得
免疫动物。
将1mg/ml的人KL-6抗原1ml分别与等体积弗氏完全佐剂均匀混合后，腹部皮下多点注射到8只6-8周 BALB/C小鼠体内。1周后，将1mg/ml蛋白1ml与等体积弗氏不完全佐剂均匀混合后，对小鼠进行腹部皮下多点注射。第3周，重复上述步骤。第4周，重复上述步骤。第四次注射后三天，断鼠尾尖取血15μl，室温静置2h，以25℃、10000rpm离心15min，取上清，通过ELISA实验检测效价。若效价检测可用即眼部取全血，室温静置2h，以25℃、6000-8000rpm离心10min，取上清，-80℃保存。
杂交瘤制备。
小鼠脱臼处死，用75%酒精消毒后，无菌取小鼠脾细胞并制成细胞悬液，将1×108个脾细胞与4×107个骨髓瘤(SP2/0)细胞融合，以50％PEG作融合剂，以HAT选择培养基培养4-10天后，以HT培养基进行培养，培养条件为5％CO2，37℃。
阳性克隆筛选。
利用ELISA反应筛选单克隆杂交瘤细胞中可分泌结合PTS域和SEA域抗原抗体的克隆，其中结合PTS域的优选克隆1株，结合SEA域的优选克隆1株。
实施例2：结合KL-6的抗KL-6双特异性抗体的结构设计
本实施例提供了可同时特异性结合KL-6蛋白PTS域和SEA域的抗KL-6双特异性抗体的结构模型，此类抗体主要实例的结构如图1所示，抗PTS特异性抗体的轻链可变区(抗PTS VL)-抗SEA特异性抗体的轻链(抗SEA VL-CL)与抗PTS特异性抗体的重链可变区(抗PTSVH)-抗SEA特异性抗体的重链(抗SEA VH-CH1-铰链区-CH2-CH3)对组成的抗KL-6双特异性抗体。
KL-6抗KL-6双特异性抗体的变体及功能性片段包括但不限于: ①抗PTS VL-抗PTS VH -铰链区-CH2-CH3-抗SEA VL-抗SEA VH; ②抗PTS VL-抗PTS VH - CH1-铰链区-CH2-CH3-抗SEA VL-抗SEA VH;③抗PTS VL-抗SEA VH -抗SEA VL-抗PTS VH。
实施例3：抗KL-6抗KL-6双特异性抗体表达载体的构建
完整的轻链（抗PTS VL-抗SEA VL-CL）编码基因通过HindIII/EcoRI克隆位点连接到pEE12.4，得到pEE12.4-PTS VL-SEA VL-LC；完整的重链（抗PTS VH-抗SEA VH-CH1-铰链区-CH2-CH3）编码基因通过HindIII/EcoRI克隆位点连接到pEE6.4，得到pEE6.4-PTS VH-SEA VH-HC；最后把pEE6.4- PTS VH-SEA VH-HC用BamHI/NotI双酶切后得到的表达盒[包含cytomegalovirus (CMV) promoter, PTS VH-SEA VH-HC, and poly(A)]克隆到pEE12.4-PTS VL-SEA VL-LC，得到表达抗KL-6双特异性抗体的单载体，命名为pEE12.4-PTS-SEA。
实施例4：抗KL-6抗KL-6双特异性抗体的制备
利用HEK293F宿主细胞表达KL-6抗KL-6双特异性抗体
将细胞密度稀释成 2×106个/毫升，摇瓶置于 5%的 CO2恒温摇床中，37℃、120rpm恒温震荡培养 10min 后开始转染。准备两支50ml 无菌离心管，在其中一支中加入10ml KPM 和 200μg 无菌质粒DNA，轻轻吹打混匀；取另一支离心管，加入 10ml KPM 和1mlTA-293 转染试剂，轻轻吹打混匀；将含有转染试剂的离心管中所有液体转移至含质粒的离心管中，轻轻吹打混匀；室温下静置 10 分钟制备出质粒-载体复合物；从恒温摇床中取出细胞，边摇边加入制备好的质粒-载体复合物，放回 CO2恒温摇床中震荡培养。
转染 24 小时后加入 1.2ml 293 细胞蛋白表达增强剂（KE-293），并加入瞬时转染营养添加剂(KT-Feed 50×)可提高产物的表达量; 转染后第 6 天测定产物表达量。
抗体纯化
将细胞培养基于5000rpm离心，收集上清并用0.22μm过滤器过滤。然后通过protein A亲和色谱柱进行纯化，并脱盐置换缓冲液，分装保存。
实施例5：唾液酸化糖链抗原KL-6试剂盒的测试
用校准品缓冲液稀释KL-6抗原，配置校准品浓度点依次为：1250U/mL，2500U/mL，5000U/mL，10000U/mL。
一种唾液酸化糖链抗原KL-6测定试剂盒的检测原理为：
该试剂盒采用胶乳增强免疫比浊法，基本原理是将KL-6抗KL-6双特异性抗体交联于胶乳颗粒上，与待测样本中KL-6发生抗原抗体结合反应，形成大的抗原-抗体复合物，浊度增加，KL-6浓度与形成的浊度成一定比例。在570nm波长下，通过检测的浊度与标准曲线比较，即可计算出样本中唾液酸化糖链抗原KL-6含量。
一种唾液酸化糖链抗原测定试剂盒的使用方法为：
将唾液酸化糖链抗原试剂盒，用全自动生化仪7180进行测试，参数如下，先加入样本3ul，再加入180ul试剂R1，37℃孵育5min，加入60ul即试剂R2，5min后读取吸光度A1，计算吸光度的差值△A＝A1-A0（起始值）；使用配套校准品进行多点定标，得到定标曲线（如图2所示）并进行线性拟合，则样本浓度(单位U/mL)可通过其检测的吸光度差值在定标曲线上计算得到。
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明抗KL-6双特异性抗体或其变体、或其功能性片段的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用，它完全可以被适用于各种适合本发明的领域，对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节和这里示出与描述的图例。
序列表
<110> 北京华睿博生物科技有限公司
<120> 抗KL-6双特异性抗体及基因、重组载体、药物、试剂盒
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Ile Leu Pro Ser Ser Gly Tyr Ala
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Lys Val Ser
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Ile Gly Ser Arg Gly Thr Tyr Thr
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Ala Arg Gly Glu Asp Tyr Arg Phe Asp Val Gly Lys Gly Val Val Tyr
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Glu Ser Val Asp Asn Tyr Gly Phe Ser Phe
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Trp Ile Ser
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Gln Gln Thr Lys Glu Val Pro Trp Thr
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Tyr Thr Gly Val Pro Asp Arg Phe Ile Gly Ser Gly Ser Ala Thr Glu
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<210> 20
<211> 351
<212> DNA
<213> 人工序列()
<400> 20
caggttcaac tgcagcaatc tggccctgaa ctggtgaaac ctggagcatc catgaaaatc 60
agctgcaaag ccagcggcta cacgtttact gtctatgtcc tcaattgggt gcgccaaaga 120
ccaggtcaag gtctggagtg gatcggaagg atcctcccaa gttctggata tgcagcctac 180
aacgcagctt tcaagggtaa aaccactctg actgtcgata aaagctctag cactgcctac 240
atggacgtgg agaccctgac tagcgaggat tccgcagtct attattgtgc caggtccaca 300
gccgctggtt acgattactg ggggcagggc acaacactca cggtctcaag c 351
<210> 21
<211> 336
<212> DNA
<213> 人工序列()
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gatgttctca tgactcagat tcctctctct ttgccggtgt ccctcggtga ccaggcctcc 60
atctcttgta agtctagcca ggccattgtg cacgccaacg ggaacaccta tctggagtgg 120
taccttcaaa aaccaggaca gagccccaag ctgttgattt acaaagtgag caacagattc 180
agcggagttc cagacagatt cagcggaagc ggtagcggca ccgactttac tttgaagatc 240
agcagggtgg aagctgaaga cctgggtgtc tactattgtt ttcagggtag ccacactccc 300
tacacatttg ggagcgggac gaagctggag atcaag 336
<210> 22
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<212> DNA
<213> 人工序列()
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caggtccagc tgcagcagtc aggagctgaa cttgtgaaac ccggagctag cgtgaagttg 60
tcatgtaaga ctagcggatt cactttcagc cactatggca tgcactggtt tcgacaggca 120
ccagaaaaag gactggaatg ggtggcctat ataggctcac gcggcaccta tactgattac 180
aacggcaaat tcagagacaa ggccaccctc actgccgaca agtctagcag cactgcctac 240
ctccagctct cttctctgac aagtgtcgac tcagctgtgt atttttgcgc acgcggcgaa 300
gattataggt tcgacgtggg gaagggggtg gtttattggg gacaggggac cacactgacc 360
gtgagttca 369
<210> 23
<211> 333
<212> DNA
<213> 人工序列()
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gatatcgtaa tgtctcagtc accatcaagc ctggccgtga gcgttggtga aaaagttaca 60
cttagttgca agagctcaga gtccgtggat aactacggtt ttagctttct ggagtggtac 120
ctgcagaagc caggacagtc ccccgtgctg ctgatttact ggatctctaa ccgctacacc 180
ggtgtgccgg acaggttcat tggaagcggc agcgccacag agttcaccct gacaattagt 240
tctgtgcagg cagaggacct ggccgactac cactgtcagc aaaccaaaga ggtaccctgg 300
acttttggtg gcggcacaaa acttgagatt aaa 333
<210> 24
<211> 786
<212> DNA
<213> 人工序列()
<400> 24
caggttcaac tgcagcaatc tggccctgaa ctggtgaaac ctggagcatc catgaaaatc 60
agctgcaaag ccagcggcta cacgtttact gtctatgtcc tcaattgggt gcgccaaaga 120
ccaggtcaag gtctggagtg gatcggaagg atcctcccaa gttctggata tgcagcctac 180
aacgcagctt tcaagggtaa aaccactctg actgtcgata aaagctctag cactgcctac 240
atggacgtgg agaccctgac tagcgaggat tccgcagtct attattgtgc caggtccaca 300
gccgctggtt acgattactg ggggcagggc acaacactca cggtctcaag cgctgaggca 360
gcagccaagg aagctgccgc taaagaagct gccgctaaag aggctgccgc taaggcacag 420
gtccagctgc agcagtcagg agctgaactt gtgaaacccg gagctagcgt gaagttgtca 480
tgtaagacta gcggattcac tttcagccac tatggcatgc actggtttcg acaggcacca 540
gaaaaaggac tggaatgggt ggcctatata ggctcacgcg gcacctatac tgattacaac 600
ggcaaattca gagacaaggc caccctcact gccgacaagt ctagcagcac tgcctacctc 660
cagctctctt ctctgacaag tgtcgactca gctgtgtatt tttgcgcacg cggcgaagat 720
tataggttcg acgtggggaa gggggtggtt tattggggac aggggaccac actgaccgtg 780
agttca 786
<210> 25
<211> 735
<212> DNA
<213> 人工序列()
<400> 25
gatgttctca tgactcagat tcctctctct ttgccggtgt ccctcggtga ccaggcctcc 60
atctcttgta agtctagcca ggccattgtg cacgccaacg ggaacaccta tctggagtgg 120
taccttcaaa aaccaggaca gagccccaag ctgttgattt acaaagtgag caacagattc 180
agcggagttc cagacagatt cagcggaagc ggtagcggca ccgactttac tttgaagatc 240
agcagggtgg aagctgaaga cctgggtgtc tactattgtt ttcagggtag ccacactccc 300
tacacatttg ggagcgggac gaagctggag atcaaggctg aggccgctgc taaagaggct 360
gccgccaaag aggctgccgc caaggaagcc gcagcaaaag ctgatatcgt aatgtctcag 420
tcaccatcaa gcctggccgt gagcgttggt gaaaaagtta cacttagttg caagagctca 480
gagtccgtgg ataactacgg ttttagcttt ctggagtggt acctgcagaa gccaggacag 540
tcccccgtgc tgctgattta ctggatctct aaccgctaca ccggtgtgcc ggacaggttc 600
attggaagcg gcagcgccac agagttcacc ctgacaatta gttctgtgca ggcagaggac 660
ctggccgact accactgtca gcaaaccaaa gaggtaccct ggacttttgg tggcggcaca 720
aaacttgaga ttaaa 735
Claims (7)
1.抗KL-6双特异性抗体或其变体、或其功能性片段，其特征在于，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 1~3所示的氨基酸序列；
所述抗PTS域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 4~6所示的氨基酸序列；
所述抗SEA域的重链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 7~9所示的氨基酸序列；
所述抗SEA域的轻链可变区的CDR1、CDR2和CDR3分别具有SEQ ID NO. 10~12所示的氨基酸序列。
2.抗KL-6双特异性抗体或其变体、或其功能性片段，其特征在于，所述抗KL-6双特异性抗体或其变体、或其功能性片段包括抗PTS域和抗SEA域，所述抗PTS域的重链可变区具有SEQ ID NO. 13所示的氨基酸序列，所述抗PTS域的轻链可变区具有SEQ ID NO. 14所示的氨基酸序列，所述抗SEA域的重链可变区具有SEQ ID NO. 15所示的氨基酸序列，所述抗SEA域的轻链可变区具有SEQ ID NO. 16所示的氨基酸序列。
3.抗KL-6双特异性抗体或其变体、或其功能性片段，其特征在于，所述抗KL-6双特异性抗体或其变体、或其功能性片段的重链双可变区具有SEQ ID NO. 17所示的氨基酸序列，所述抗KL-6双特异性抗体或其变体、或其功能性片段的轻链双可变区具有SEQ ID NO. 18所示的氨基酸序列。
4.编码权利要求1~3任一所述的抗KL-6双特异性抗体或其变体、或其功能性片段的基因。
5.包括权利要求4所述基因的重组载体。
6.药物，其特征在于，包括权利要求1~3任一所述的抗KL-6双特异性抗体或其变体、或其功能性片段。
7.试剂盒，其特征在于，包括权利要求1~3任一所述的抗KL-6双特异性抗体或其变体、或其功能性片段。
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| WO2018174544A3 (ko) * | 2017-03-21 | 2018-11-08 | 주식회사 펩트론 | Muc1에 특이적으로 결합하는 항체 및 그의 용도 |
| CN109633148A (zh) * | 2018-12-27 | 2019-04-16 | 恩碧乐(杭州)生物科技有限公司 | Kl-6检测乳胶凝集试剂 |
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| WO2018174544A3 (ko) * | 2017-03-21 | 2018-11-08 | 주식회사 펩트론 | Muc1에 특이적으로 결합하는 항체 및 그의 용도 |
| CN109633148A (zh) * | 2018-12-27 | 2019-04-16 | 恩碧乐(杭州)生物科技有限公司 | Kl-6检测乳胶凝集试剂 |
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